In recent years, it has been reported that immune aging had an important impact on tumor development. A research team from the Shanghai Institute of Nutrition and Health (SINH) of the Chinese Academy of Sciences (CAS) revealed that aging specifically impaired the generation of CD8⁺ tissue-resident memory T cells (TRM) and thus compromised the antitumor defensive activity of aged CD8⁺ T cells.

With the aging process, the risk of developing cancer significantly increases. Immune aging is a common physiological phenomenon among aging individuals, and it is a degenerative change in the immune system that occurs with aging, leading to a decline in immune response and ultimately triggering diseases including tumors. Among immune system, CD8⁺ T cells are the main defensive adaptive immune cells protecting against tumor cells. However, the mechanism by which aging impairs the antitumor response of CD8⁺ T cells was still unclear.

To investigate the intrinsic role of aging on CD8+ T cell function, Prof. XIAO Yichuan's group from SINH, in collaboration with other groups, isolated CD8+ T cells from young or aged mice, and then adoptively transferred them into Rag1-/- mice, single-cell RNA sequencing (scRNA-seq) of tumor infiltrating CD8⁺ T cells showed that the percentage of TRM cell subpopulation was decreased in aged group. Next, to figure out how aging causes the decline of CD8⁺ TRM cells, the researchers used multifactorial gene screening, and found that high expression of E3 ubiquitin ligase BFAR inhibited the production of TRM cells in CD8⁺ T cells derived from elderly individuals. Mechanistically, E3 ligase BFAR suppressed cytokine-induced JAK2 signaling by activating JAK2 deubiquitination through deubiquitinase USP39, thereby limiting downstream STAT1-mediated TRM reprogramming.

Based on the identified key E3 ligase BFAR in CD8⁺ T cells function, the researchers applied deep learning combined with molecular simulation to screen a library of approximately 1,474,607 compounds and obtained iBFAR2, a small molecule compound that abolished USP39 ubiquitination, inhibited JAK2 deubiquitination and thus promoted STAT1 phosphorylation and TRM differentiation, thereby boosting antitumor immunity in aged mice.

In addition, researchers found that targeting BFAR could not only revive the antitumor activity of aged CD8⁺ T cells, but also enhance the sensibility of PD-1 blockade-based immunotherapy. PD-1/PD-L1 immune checkpoint blockade therapy has become a major weapon in fighting advanced tumors; however, most patients are refractory to the therapy or acquire resistance, especially those who are elderly. 

In summary, this study revealed the role and molecular mechanism of aging in compromising anti-tumor immune response of CD8⁺ T cells. Further investigation of inhibitors targeting BFAR will promote the development of cancer immunotherapy in elderly patients and patients resistant to anti-PD-1 therapy.

Results of the study entitled "Age-related decline in CD8⁺ tissue resident memory T cells compromises antitumor immunity" was published in Nature Aging on Nov. 26, 2024.

This research was supported by the grants from CAS Project for Young Scientist in Basic Research, the Strategic Priority Research Program of CAS, the National Natural Science Foundation of China, the National Key R&D Program of China, the Shanghai Municipal Science and Technology, Natural Science Foundation of Hebei Province and CAS Key Laboratory of Tissue Microenvironment and Tumor. 

Working model of aging compromise CD8⁺ T cell-mediated antitumor immunity.
 (Image provided by Prof. XIAO Yichuan's group)

Media Contact: 
WANG Jin (Ms.) 
Shanghai Institute of Nutrition and Health, 
Chinese Academy of Sciences 
Email: wangjin01@sinh.ac.cn
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